The reinforcing effects of intra-cranial self-stimulation (ICS), like those of natural rewards and abused drugs, involve the dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) (Wise, 1996). We previously examined the activity of neurons in the core of the NAc simultaneously with subsecond dopamine release from the same electrode in animals engaged in an ICS task (Cheer et al., 2005). The only neuronal responses observed were time-locked to the electrical stimulation but preferentially mediated by GABA. However, our most recent findings in the NAc shell show coincident changes in firing and subsecond dopamine release occurring at cues signaling reward availability that are functionally linked via D1 receptor activation during ICS (Cheer et al., 2007b, Appendix A). Accumulating evidence suggests that endogenous cannabinoids regulate reward processing in the brain, including ICS, by modulating neurotransmitter levels including GABA and dopamine (Gardner, 2005). Given these findings, we propose three experiments to investigate the mechanisms through which the shell of the NAc encodes reward-related information during ICS. The first experiment will examine the effects of manipulating endogenous cannabinoid signaling on patterned cell firing and subsecond dopamine release in the shell during learning of ICS. Specifically, a cannabinoid receptor antagonist or an endogenous cannabinoid reuptake blocker (Pertwee, 2005) will be injected systemically prior to the start of the first operant session to determine the role of endogenous cannabinoid tone in ICS acquisition, and its impact on the generation of patterned activity and phasic dopamine release. The second experiment will evaluate reinforcement-specific cell firing and subsecond dopamine release in the shell during maintenance of ICS in well-trained animals. For this experiment the cannabinoid receptor antagonist and the endogenous cannabinoid uptake blocker will be delivered during the ICS session to assess whether behavioral execution of ICS and associated neurophysiological and neurochemical responses are controlled by endogenous cannabinoids. The third experiment will assess, with the aid of intracerebral microinjections, whether endogenous cannabinoid signaling specifically in the VTA, modifies ICS execution and associated neural and dopamine release patterns in the NAc. Altogether, these experiments should provide an unprecedented insight into accumbal encoding of reward and its physiological modulation by endogenous cannabinoids.